N-acetyl-n-(cyclopropyl-4-pyrimidinyl)-sulphanilamides as antibacterial agents

ABSTRACT

N1-Acetyl-N1-(4-pyrimidinyl)-sulphanilamides substituted by a cyclopropyl group in 2-, 5- or 6-position, which are antibacterial agents against gram-positive bacteria such as staphylococci, streptococci, pneumonococci and against gramnegative bacteria such as salmonella, oscherichia and klebsiella strains; pharmaceutical compositions containing the aforesaid pyrimidines as antibacterial ingredients, and a method of treating diseases caused by such bacteria, by administration of such pyrimidines or pharmaceutical compositions containing them.

United States Patent 151 3,683,082 Zimmermann [4 Aug. 8, 1972 [54]N-ACETYL-N-(CYCLOPROPYL-4- 3,422,098 1/1969 Schmidt et al ..760/239.75

PYR IDI AM! As gi g il'ggg g f DES FOREIGN PATENTS 0R APPLICATIONS [72]Inventor: Markus Zimmermann, Riehen, 670903 4/1966 Belgium SwltzerlandPrimary Examiner-Jerome D. Goldberg [73] Assignee: Geigy ChemicalCorporation, Ard- Attorney-Karl F. Jorda and Martin J. Spellmansley,N.Y. 22 Filed: Feb. 9, 1970 [57] P pp No: 14,704N-Acetyl-N-(4-pyrimidinyl)-sulphanilamides sub- Related us. ApplicationData [62] Division of Ser. No. 662,901, March 14, 1967,

Pat. No. 3,528,967.

52 US. Cl ..424/229 51 Int. Cl. ..'..A6lk 27/00 [58] Field of Search..424/229 [56] References Cited UNITED STATES PATENTS 2,891,949 6/1959Webb et aI. ..260/239.75

stituted by a cyclopropyl group in 2-, 5- or 6-position, which areantibacterial agents against gram-positive bacteria such asstaphylococci, streptococci, pneumonococci and against gram-negativebacteria such as salmonella, oscherichia and klebsiella strains;pharmaceutical compositions containing the aforesaid pyrimidines asantibacterial ingredients, and a method of treating diseases caused bysuch bacteria, by administration of such pyrimidines or pharmaceuticalcompositions containing them.

6 Claims, No Drawings FIELD OF THE INVENTION The present inventionconcerns new sulphanilamide derivatives, processes for the productionthereof, medicaments which contain the new compounds and the usethereof.

SUMMARY OF THE INVENTION The invention provides in a first aspect novelsulphanilamido-pyrimidines of the formula wherein a single one of R,, Rand R represents the cyclopropyl group and, when not representing thecyclopropyl group,

R and R independently of each other represent hydrogen, halogen atoms,low alkyl, alkoxy or alkylthio groups, and

R represents hydrogen, a low alkyl or alkoxy group; these novelcompounds have an excellent antibacterial action, while beingpractically harmless to mammals when used in antibacterially effectivedosages, and are, therefore, useful as antibacterial agents in thetreatment of infectious diseases.

In a second aspect, the invention provides pharmaceutical compositionscontaining an antibacterially effective amount of a compound accordingto the invention and a phannaceutically acceptable carrier therefor.

A third aspect of the invention provides fora method of treatinginfectious diseases in mammals by administering to an individualsuffering therefrom an antibacterially effective amount of a compoundaccording to the invention.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENT In thecompounds of general formula I, R R and R as alkyl groups are, e.g. themethyl, ethyl, propyl or the isopropyl group and, as alkoxy groups theyare, e.g. the methoxy, ethoxy, propoxy or the isopropoxy group. Inaddition, as alkylthio groups, R, and R are, e.g. the methylthio or theethylthio group.

As halogen atoms R, and/or R represent especially chlorine or bromine,but most preferably chlorine.

A preferred compound is N-acetyl-N 6-cyclopropyl-4-pyrimidinyl)-sulphanilamide.

To produce these new compounds, a compound of general formula II whereinX represents a group which can be converted by reduction into the aminogroup, and R R, and R, have the meanings given in formula I, is reducedor, if desired, a compound of the general formula II wherein X is asubstituted methylene amino group is partially hydrolyzed, i.e. the N-acetyl group is maintained. Groups which can be converted by reductioninto the amino group are, e.g. the benzyloxycarbonylamino group(carbobenzyloxyamino group) and the nitro gro p, so, e.g. substitutedmethylene amino groups such as the benzylidene amino group as well assubstituted azo groups such as the phenylazo or pdimethylaminophenylazogroup. In the azo compounds mentioned, the amino group is formed fromthe nitrilo radical bound to the benzene ring by one of its threevalences. A corresponding nitrilo radical is also present in theN,N-diacetyl-azobenzene-4,4-disulphonarnides both sulphonamide groups ofwhich carry identical 4- pyrimidinyl radicals substituted correspondingto the definition of R R and R and on the reduction of which twomolecules of a compound of general formula I are formed. The reductionto the amino group of groups X which can be reduced or split byreduction can be performed catalytically, e.g. by means of hydrogen inthe presence of a palladium catalyst or of Raney nickel, in an inertorganic solvent such as dioxane or ethanol, but also other processessuch as the reduction of nitro groups and also azo groups by means ofiron in acetic or hydrochloric acid can be used. The benzylidene aminogroup in particular is suitable as substituted methylene amino group Xwhich can be split by hydrolysis. Compounds of general formula II whichcontain this group can be partially hydrolyzed under careful conditions,e.g. by heating with water to or higher, to form compounds of generalformula 1.

Starting materials of the general formula II can be obtained, e.g. byreacting a derivative of a p-substituted benzene sulphonic acidcorresponding to the general formula III x- S0z-A1Y with a compound ofthe general formula IV N R2 j-Ri R3:/N

iii-z 1v wherein 0 one of the two symbols A and A represents the 6 iminogroup (NH) and the other the direct bond, and Y and Z representsreactive radicals which can be split off together, and

R,, R, and R have the meanings given in Formula I wherein R,, R and Rhave the meanings given in formula I and X has that given in formula II,and reacting the latter compound with acetanhydride, in the presence ofpyridine, at room temperature or moderately elevated temperature. Forexample, acetanhydride is used in multiple excess and, together withpyridine, serves at the same time as reaction medium. Should thecompound obtained of general formula V contain halogen atoms,particularly chlorine atoms as radicals R, and/or R they can, ifdesired, be reacted before the acetylation with a metal compound of alow alkanol or alkane thiol in order to replace the halogen atoms(s) byone or two low alkoxy or alkylthio groups. The various possibilities forthe symbols A,, A Y and Z, the performance of the reaction of thecorresponding compounds of the general formulas III and IV and also theproduction of the latter group of compounds, which are new substances,is further illustrated below.

If, in the compound of general formula III, A, is the imino group and,in that of general formula IV, A is the direct bond, Y is, e.g. amonovalent cation, particularly an alkali metal ion or the normalequivalent of a polyvalent cation, and Z is a halogen atom, particularlya chlorine or bromine atom, also a cyanamino or nitroamino radical or,provided R, and/or R is/are not (an) alkylthio group(s), it is a lowalkylsulphonyl radical. In addition, in compounds of the general formulaIV, Z can also represent the grouping of formula VI Guru-01 CH3 CH1 (VI)On the other hand, if A, is the direct bond and A, is the imino group,then Y is, e.g. a halogen atom, particularly a chlorine atom, or anacyloxy radical, e.g. a radical of the general formula VII wherein X hasthe meaning given in formula II and Z represents a hydrogen atom.

The reactions of compounds of general formula III with those of generalformula IV are performed, e.g. in a suitable organic solvent such asdimethyl formarnide, acetamide, N,N-dimethyl acetamide or dimethylsulphoxide, while heating. If an acid is formed as liberated compoundY-Z, the reaction is performed in the presence of an acid binding agentsuch as pyridine or trimethylamine in methylene chloride.

Reactions of compounds of the general formula V, wherein R, and/or Rrepresent(s) halogen with metal compounds, in particular alkali metalcompounds such as sodium compounds, of low alkanols, are most simplyperformed in the alkanols concerned as solvent while heating, e.g. atboiling temperature or at a raised temperature, in a closed vessel. Inaddition, dimethyl sulphoxide dimethyl formamide can also be used assolvent. The sarne solvents and temperatures are also suitable for thereaction of compounds of general formula V wherein R, and/or Rrepresent(s) halogen,

(VII) with alkyl mercaptides, in particular with alkali metal alkylmercaptides.

To produce compounds of general formula IV wherein A, represents thedirect bond, Z has the meaning given in formula IV and R, that given informula I, R represents a cyclopropyl radical and R is hydrogen, theknown low B-oxo-cyclopropane propionic acid alkyl esters, particularlythe ethyl or methyl ester, can be used as starting material. These arecondensed with thiourea, low O-alkyl isoureas or S-alkyl isothioureas orwith amidines of low alkanoic acids such as formamidine and acetamidine,to form 6-cyclopropyl-2- thiouracil(6-cyclopropyl-2-mercapto-4-pyrimidinol low 2-alkoxyor 2-alkylthio-6-cyclopropyl-4- pyrimidinol, or 6-cyclopropyl-4-pyrimidinol, or 2-alkyl-6-cyclopropyl-4-pyrimidinols respectively. If desired,6-cyclopropyl-2-thiouracil can be reduced, e.g. with Raney nickel in thepresence of ammonia, to form 6cyclopropyl-4-pyrimidinol or it can bealkylated, e.g. with dialkyl sulphates or low alkyl halides in thepresence of potassium carbonate to form corresponding 2-alkylthiocompounds or, finally, it can be converted by boiling with 10 percentaqueous chloracetic acid into 6-cyclopropyl uracil. By treating the 4-pyrimidinol derivatives mentioned above with phosphorus oxychloride,e.g. in the presence of diethyl aniline, the corresponding4-chloropyrimidine derivatives which are embraced by general formula IVare obtained, and on treating 6-cyclopropyl uracil analogously,2,4-dichloro-6-cyclopropyl-pyrimidine, which is also embraced by thisformula, is obtained. By reacting the monochloro compounds mentionedabove with trimethylamine, N-(6-cyclopropyl-4-pyrimidinyl)-N,N,N-trimethyl ammonium chlorides substituted in the 2-position by R,with the exception of the cyclopropyl radical are obtained as furthercompounds of general formula IV. Corresponding compounds having a lowalkylsulphonyl radical as radical Z which can be split ofi are produced,e. g. by reacting 4- chloro-6-cyclopropyl-pyrimidine, 2,4-dichloro-6-cyclopropyl pyrimidine or 2-alkoxyor 2-alkyl- 4-chloro-6-cyclopropyl-pyrimidines with alkali metal salts of low alkanethiols and oxidizing the 4-alkylthio compounds obtained, e.g. withperacetic acid. If the above sequence of reactions is begun withIowa-alkylor a-alkoxy- B-oxocyclopropane propionic acid alkyl estersinstead of with the corresponding esters not having ana-substituent,then completely analogous compounds of general formula IV containing anadditional low alkyl or alkoxy group in the 5-position are ob tained.The condensation components mentioned, aalkyl-B-oxo-cyclopropanepropionic acid alkyl esters, can be obtained, e.g. fromB-oxo-cyclopropane propionic acid alkyl esters and alkyl iodides in thepresence of a low sodium alcoholate and the correspondinga-alkoxy-B-oxo-cyclopropane propionic acid alkyl esters can be obtainedfrom a-diazo-B-oxocyclopropane propionic acid alkyl esters and a lowalkanol in the presence of copper and borotn'fluoride etherate.

To produce compounds of the general formula IV wherein A, is the directbond, Z has the meaning given in formula IV and R; has that given informula I, R is a cyclopropyl radical and R, is hydrogen, firstcyclopropane carboxamidine is condensed with lowalcyclopropyl-4,6-dihalogen pyrimidines. The latter pyrimidinederivatives having a low alkyl or alkoxy radical as R are produced byusing, in the sequences of reactions mentioned above, a-alkylor a-alkoxyderivatives of low alkanoyl acetic acid alkyl esters instead of theseesters themselves or by using low a -alkyl malonic acid dialkyl estersinstead of the low malonic acid dialkyl esters.

Compounds of the general formula IV wherein A is the direct bond, Z hasthe meaning given in formula IV, R, and R have those given in formula Iand K, is a cyclopropyl radical can be produced, for example, startingfrom low cyclopropyl malonic acid alkyl esters or 2-cyclopropyl alkanoylacetic acid alkyl esters, par-' ticularly 2-cyclopropyl formyl-aceticacid alkyl esters and -acetoacetic acid alkyl esters. On condensingthese with amidines of low alkanoic acids such as formamidine andacetamidine, with low O-alkyl isoureas or S-alkyl isothioureas,5-cyclopropyl-4,6-pyrimidine diol, 2-alkyl-, 2-alkoxyor 2-alkylthio-4,6-pyrimidine diols or 5-cyclopropyl-4-pyrimidinols or 6-alkyl-5-cyclopropyl-4-pyrimidinols correspondingly substituted in the 2-positionare obtained. By reaction with inorganic acid halides such as phosphorusoxychloride or thionyl chloride, the hydroxyl groups are replaced byhalogen atoms, particularly chlorine atoms and, e.g.,5-cyclopropyl-4,65- cyclopropyl-4-halogen pyrimidines or5-cyclopropyl-6- alkyl-4-halogen pyrimidines which can be substituted asdefined in the 2-position and which are embraced by general formula IVare obtained.

Instead of producing pyrimidine derivatives direct by using formamidineor S-alkyl isothioureas in the above mentioned cyclization reactionssuitable therefor, in which pyrimidine derivatives R, is hydrogen or alow alkylthio radical, also thiourea can be used as reaction component.In this case, 5-cyclopropyl-2-mercapto-4,6 -pyrimidine diol,S-cyclopropyl-Z-thiouracil or low 6- alkyl-S-cyclopropyl-2-thiouracilsare obtained as direct reaction products. These are then reduced eitherto compounds having hydrogen as R, or are alkylated to compounds havinga low alkylthio radical as R, or, finally, are hydrolyzed, e.g. byboiling with 10 percent aqueous chloroacetic acid, to S-cyclopropylbarbituric pounds,

acid, S-cyclopropyl uracil or low 6-alkyl-3cyclopropyl uracils. Thesehydroxyl compounds are then converted in the usual way into thecorresponding halogen comi.e. into 5-cyclopropyl-2,4,6-trihalogenpyrimidines, 5-cyclopropyl-2,4-dihalogen pyrimidines or low6-alkyl-5-cyclopropyl-2,4-dihalogen pyrimidines.

Further compounds of general Formula IV having halogen as radical Z areobtained from the above and previously mentioned, optionally2-substituted 5- cyclopropyl-4,6-dihalogen pyrimdines by reaction withequimolar amounts of alkali metal compounds of low alkanols or alkanethiols. Compounds of the general formula IV having different reactiveradicals Z are obtained, e.g. by reacting the compound mentioned abovewherein Z is a halogen atom with trimethylamine or with alkali metalsalts of low alkane thiols and then oxidizing the 4-alkylthio compoundsobtained to form 4-alkylsulphonyl compounds, e.g. with peracetic acid.

Compounds of the general formula IV wherein A is the irnino group and Zis hydrogen while R R and R have the meanings given in formula I, i.e.2-amino-6- cyclopropyl pyrimidinine, 4-amino-6-cyclopropyl pyrimidine,4-arnino-2-cyclopropyl pyrimidine, 4- arnino-S-cyclopropyl pyrimidineand derivatives thereof substituted as defined in the free positions canbe obtained, e.g. by reacting the corresponding 4- halogenor4-alkylsulphonyl- 6-cyclopropyl pyrimidines, -2-cyclopropyl pyrimidinesor -5- cyclopropyl pyrimidines optionally substituted in the 2- and/or6-position(s) mentioned above with ammonia. However, in some of thecyclization reactions mentioned above, a-cyano ketones can be usedinstead of a-acylacetic acid alkyl esters or cyanoacetic acid alkylesters can be used instead of malonic acid dialkyl esters. In this way,substituted 4-amino-pyrimidines or substituted 4-amino-6-pyrimidinolsembraced by general formula IV are obtained. Starting materials ofgeneral formula IV are obtained from the latter by converting them intosubstituted 4-amino-6-halogen pyrimidines and, optionally, furthermodifying into substituted 4-amino-6-alkoxy pyrimidines or4-amino-6-alkylthio pyrimidines.

The new sulphanilamide derivatives corresponding to the general formulaI are suitable for the preparation of medicaments for internal orexternal use, e.g. for the treatment of infections caused by grampositive bacteria such as staphylococci, streptococci, pneumococci aswell as gram negative bacteria such as Salmonella typhi, Erchen'chi coliand Klebsiella pneumoniae.

The new active substances are administered per 0s. The daily dosagesvary between 200 and 5,000 mg for adult patients. Suitable dosage unitssuch as tablets preferably contain 150 700 mg. of an active substanceaccording to the invention. Also corresponding amounts of forms for usenot made up into single dosages such as syrups, ointrnents or powderscan also be used.

Dosage units for oral administration preferably contain between 60 andpercent of a compound of general formula I as active substance. They areproduced by combining the active substance with, e.g., solid,pulverulent carriers such as lactose, saccharose, sorbitol, mannitol;starches such as potato starch, maize starch or amylopectin, alsolaminaria powder or citrus pulp powder; cellulose derivatives orgelatines, optionally with the addition of lubricants such as magnesiumor calcium stearate or polyethylene glycols of suitable molecularweights, to form tablets.

The following prescription further illustrates the production oftablets:

50.000 kg of N -acetyl-N-(6-cyclopropyl-4- pyrimidinyl)-sulphanilamideare mixed with 2.000 kg. of stearic acid in 4 liters of ethanol and thewhole is mixed for 15 minutes. 1.200 kg. of gelatine in 16 liters ofdistilled water are then added and the mass is kneaded for 20 minutes.As soon as it is sufficiently moist, it is granulated through a sieve(25 meshes/sq. cm) and dried. The dried granules are again sieved (60'mesheslsqcm) and then mixed for 1 hour with 4.000 kg. of potato starch,1.200 kg. of talcum and 0.400 kg. of sodium carboxymethyl cellulose. Themass obtained is pressed into 100,000 tables each weighing 600 mg. andcontaining 500 mg. of active substance.

The following examples further illustrate the production of the newcompounds of general formula I and of hitherto undescribed intermediateproducts but they in no way limit the scope of the invention. Thetemperatures are given in degrees Centigrade.

EXAMPLE 1 a. 23.2 g of thiourea and then 34 g. of B-oxocyclopropanepropionic acid ethyl ester are added to a solution of g. of sodium in220 ml. of dry ethanol. The mixture is stirred and heated at an oil bathtemperature of 8085. After 10 minutes the mixture thickens whereuponanother 50 ml. of dry ethanol are added. The mixture is stirred for 7hours at 80-85 bath temperature. The reaction mixture is concentratedunder 12 Torr. On adding water to the residue a cloudy solution isformed. This is extracted three times with ether whereupon it becomescompletely clear. The pH of the aqueous solution is then adjusted to 2 3with 5N hydrochloric acid, the precipitate is filtered off under suctionand dried over phosphorus pentoxide in a vacuum desiccator. The6-cyclopropyl-2-tl'iiouracil (6-cyclopropyl-2-mercapto-4-pyrimidinol)obtained melts at 234-237 with gas development. It is sufficiently purefor the following reactions. To attain a substance sufficiently pure foranalysis it is recrystallized from aqueous ethanol whereupon it thenmelts at 23623 8 with gas development.

b. 14.5 g. of crude 6-cyclopropyl-2-thiouracil are stirred into amixture of 230 ml. of water and 23 ml. of concentrated ammonia and themixture is heated to' 80. Fifty-two g. of moist Raney nickel are thenadded in portions whereupon the mixture foams. When the metal has beenadded, the mixture is stirred at a bath temperature of 120-l30 for 1V2hours. After the nickel has settled, the solution is decanted as far aspossible and the catalyst is removed from the remainder of the solutionby filtration under suction. The nickel is washed twice with 100 ml. ofboiling water each time. The filtrates are combined and concentrated.The crude residue, 6-cyclopropyl-4 pyrimidinol, weighs 7.7 g. and meltsat l63l65. During the concentration, part of the substance passes overwith the steam. Thus, the pH of the distillate is adjusted to 6 7 and itis continuously extracted with ether for 24 hours. An additional 1.4 g.of 6-cyclopropyl-4- pyrimidiol is gained.

0. 36 m1. of phosphorus oxychloride and 7.2 ml. of N,N-diethyl anilineare mixed and 7.2 g. of crude 6- cyclopropyl-4-pyrimidinol are sprinkledin. The mixture is heated for 30 minutes at a bath temperature of 90 andthe brown solution obtained is concentrated in vacuo. The oily residueis poured onto ice and the emulsion is extracted three times with ether.The ether solution is washed first with ice cold 5 percent sodiumbicarbonate solution and then with saturated sodium chloride solution.The solution is dried over sodium sulphate and the ether is distilledoff whereupon 6.7 g. of crude 4-chloro-6-cyclopropyl pyrimidine remain.It is distilled over a short Vigreux column; under 12 Torr it passesover at 97-98 and 4.3 g. of a colorless oil are obtained whichcrystallizes after a short time.

d. 3.9 g. of 4-chloro-6-cyclopropyl pyrimidine are dissolved in ml. of asolution obtained by saturating anhydrous ethanol with ammonia gas underice cooling. The solution is heated for 5 hours in an autoclave at 95and then the reaction mixture is evaporated to dryness in vacuo. Theresidue is shaken with 10 ml. of 2N hydrochloric acid and 30 ml. ofether, the phases are separated and the ethereal phase is againextracted with 10 ml. of 2N hydrochloric acid. The aqueous acid extractsare combined and made strongly akaline with lON sodium hydroxidesolution whereupon the crude amine precipitates. It is dissolved inether and the ethereal solution is dried with sodium sulphate. Pure 4-amino-6-cyclopropyl pyrimidine is obtained by crystallization fromether/hexane, M.P. l5 ll53.

e. 3.0 g. of 4-amino-6-cyclopropyl pyrimidine are dissolved in 30 ml. ofdry pyridine and 1.8 g. of N- benzyloxycarbonylsulphanilyl chloride (cf.H. Gregory, J.Chem.Soc. 1949, 2066) are added in portions. The reactionmixture is stirred, first for 14 hours at room temperature and then for2 hours 60 and then evaporated to dryness in vacuo. The residue isstirred with water and the mixture obtained is made strongly acid by theaddition of concentrated hydrochloric acid. The precipitate is filteredoff and dissolved in acetic acid and the N-benzyloxycarbonyl-N-(6-cyclopropyl- 4-pyrimidinyl)-sulphanilamide iscrystallized by the addition of water. It is filtered off and dried for16 hours under high vacuum at 90-100. M.P. 203204.

f. A mixture of 50 ml. of pyridine, 10 ml. of acetanhydride and 10 g. ofN-benzyloxycarbonyl-N-(6- cyclopropyl-4-pyrimidinyl)-sulphanilamide isstirred for 40 hours at 40, a further 5 ml. of acetanhydride being addedafter the 20th hour. After cooling, the reaction mixture is diluted with50 ml. of ether, shaken with a small amount of active charcoal, filteredand 500 ml. of hexane are slowly added to the filtrate. The precipitatedcrude product is filtered off under suction and recrystallized fromtetrahydrofuran and ether. N-benzyloxycarbonyl-N-acetyl-N-(6-cyclopropyl-4-pyrimidinyl)-sulphanilamide is obtained, M.P. l90-l9 2.

g. Five g. of the crude product according to (f) are dissolved in 500ml. of dry dioxane and the solution is hydrogenated in the presence of10 g. of palladium-aluminum oxide catalyst (0.7% Pd). After 3 hours, nomore starting material can be traced by thin layer chromatography. Themixture is filtered and the filtrate is lyophilized. Practically pure,pulverulent N-acetyl-N- (6-cyclopropyl-4-pyrimidinyl)-sulphanilamideremains as residue. After crystallization from tetrahydrofuran/ether,the product melts at l 17-l 18.

The following compounds, for example, can be produced in an analogousway if, in step (d), the corresponding substituted chloropyrimidine isused or in step (e) the corresponding substituted aminopyrimidine isused:

sulphanilamide (using 4-chloro-2-cyclopropyl pyrimidine);

N-acetyl-N-(6-cyclopropyl-2-methyl-4-pyrimidinyl)-sulphanilamide (using4-chloro-6- cyclopropyl-2-methyl pyrimidine, oily);

N-acetyl-N-(2-cyclopropyl-6-methyl-4-pyrimidinyl)-sulphanilamide (using4-chloro-2- cyclopropyl-6-methyl pyrimidine, B.P.104107 12 Torr.

EXAMPLE 2 a. 17.6 g. of a-diazo-B-oxo-cyclopropane propionic acid ethylester (cf. L.J.Smith & S. McKenzie, J. Org. Chem. 15, 74 (1950)) aredissolved in 135 ml. of dry methanol. This solution, with the additionof 1 g. of copper powder and 4 drops of borotrifluoride etherate, isheated at a bath temperature of 6070. At first strong development ofnitrogen occurs which is completed after 2 hours. The reaction mixtureis then filtered and the filtrate is evaporated to dryness. The oilwhich remains is fractionated whereupon pure methoxy-B-oxo-cyclopropanepropionic acid ethyl ester is obtained, B.P. 6061/0.l Torr. I

b. 2.25 g. of sodium are added to 45 ml. of dry ethanol whereupon 8.75g. of thiourea and then 12.25 g. of the ester obtained according toexample 2(a) are' added. The mixture is then refluxed for 7 hours. Theethanol is distilled off in vacuo, the residue is dissolved in 25 ml. ofwarm water and the solution is decolorized with 25 ml. of activecharcoal. The active charcoal is filtered off and the pH of the filtrateis adjusted to 6 with 5N hydrochloric acid. The suspension obtained isthen left to stand for 1 hour at and the crude2-mercapto--methoxy-6-cyclopropyl-4-pyrimidinol is filtered off undersuction. It is washed with water and dried in vacuo whereupon it meltsat 208210 with decomposition. Recrystallization of the crude productfrom ethanol yields the pure compound which melts at 2 l l2 1 3 underdecomposition.

c. Eight g. of the crude mercapto compound produced according to example1 (b) are added to 100 ml. of distilled water and 10 ml. of percent (byweight) of aqueous ammonia. The mixture is heated to 7080 whilestirring, 24 g. of Raney nickel in the form of a moist paste are addedin portions whereupon the suspension is heated for 1% in a ll0-120 hotbath while continuing stirring. The precipitate is filtered off andwashed twice with hot water. The filtrates are evaporated to dryness invacuo and the residue is dried over phosphorus pentoxide. he crude5-methoxy-6- cyclopropyl-4-pyrirnidinol obtained melts at ll3-1l6Sublimation of the crude product at 90-100/0.l Torr yields the purecompound; it melts at 120l 22.

d. 5.7 g. of the crude 5-methoxy-6-cyc1opropyl-4- pyrimidinol are addedto 36 ml. of ice cold phosphorus oxychloride and then 2.6 ml. ofN,N-dimethyl aniline are added. The mixture obtained is stirred at abath temperature of -100 for 1% hours, then the excess phosphorusoxychloride is distilled off under vacuum and the residue is poured ontoice. The suspension obtained is extracted three times with 50 ml. ofether each time, the ether extract is washed, first with water, thenwith 5 percent (by weight) of sodium hydrogen carbonate solution andagain with water, dried over sodium sulphate and concentrated. Theresidue, crude, oily 4-chloro-5-methoxy-6-cyclopropyl pyrimidine is useddirect for the following reaction.

- pyrirnidinyl)-sulphanilamide is obtained analogously to example 1 (d)to (g) from the 4-chloro-5-methoxy-6- cyclopropyl pyrimidine.

I claim:

1. A method of treating a bacterial infective disease, comprisingadministering to a mammal afflicted thereby an antibacterially effectiveamount of a compound of the formula N R \LERI K/ JJO CII;

wherein a single one of R R and R represents cyclopropyl, and, when notrepresenting cyclopropyl, R and R independently of each other representhydrogen, halogen, lower alkyl, lower alkoxy or lower alkylthio, and Rrepresents hydrogen, lower alkyl or lower alkoxy.

2. A method as claimed in claim 1, wherein each of R and R are hydrogenand R is cyclopropyl.

3. A method as claimed in claim 1, wherein R is hydrogen, R iscyclopropyl and R is methoxy.

4. An antibacterial therapeutic composition comprising anantibacterially efiective amount of a compound of the formula R2 //NW-RIRak/ A STAS PATENT FFIfiE immi" to Patent No. 32 311 Dated Augusts, 1972fl j MARKUS ZIMWRMANN It is certified that error appears in theabove-identified patent and 'that said Letters Patent are herebycorrected as shown below:

Column 1, insert [30] Foreign Application Priority Data April 13, 1966SwitzerlandMU...535O/66 [73] Assignee should read CIBA-GEIGYCorporation.

Signed and sealed this 23rd day of April' 197A.

(SEAL) Attest:

EDWARD I-I.FLETCHER,JRO Ca MARSHALL DANN Attesting Officer Commissionerof Patents

2. A method as claimed in claim 1, wherein each of R1 and R3 arehydrogen and R2 is cyclopropyl.
 3. A method as claimed in claim 1,wherein R1 is hydrogen, R2 is cyclopropyl and R3 is methoxy.
 4. Anantibacterial therapeutic composition comprising an antibacteriallyeffective amount of a compound of the formula wherein a single one ofR1, R2 and R3 represents cyclopropyl, and, when not representingcyclopropyl, R1 and R2 independently of each other represent hydrogen,halogen, lower alkyl, lower alkoxy or lower alkylthio, and R3 representshydrogen, lower alkyl or lower alkoxy- and a pharmaceutically acceptablecarrier therefor compatible therewith.
 5. An antibacterial therapeuticcomposition as claimed in claim 4, wherein each of R1 and R3 arehydrogen and R2 is cyclopropyl.
 6. An antibacterial therapeuticcomposition as claimed in claim 4, wherein R1 is hydrogen, R2 iscyclopropyl and R3 is methoxy.